Phase 3 STELLAR-316 tests zanzalintinib with or without pembrolizumab for ctDNA-positive, scan-negative colorectal cancer

Exelixis’ randomized Phase 3 STELLAR-316 study enrolls resected stage II/III colon or rectal adenocarcinoma that is MSS or MSI-low/pMMR, with molecular residual disease detected by the Signatera ctDNA assay after definitive treatment and no radiographic evidence of disease. Participants are assigned to zanzalintinib plus subcutaneous pembrolizumab/berahyaluronidase alfa (MK-3475A), zanzalintinib alone, or placebo, with treatment for up to 2 years under the protocol.

Zanzalintinib inhibits VEGF receptors, MET, and TAM-family kinases including AXL and MER; pembrolizumab blocks PD-1. The primary question is whether this targeted therapy, with or without checkpoint blockade, improves disease-free survival. ctDNA clearance is a related biomarker outcome, not a substitute for proving fewer recurrences. The study addresses a high-risk, scan-negative setting where routine surveillance follows completion of curative-intent treatment and no broadly established systemic standard exists solely because ctDNA remains positive in MSS disease. A placebo comparison here does not mean withholding known effective treatment for visible recurrent cancer.